Melatonin modulates metabolic remodeling in HNSCC by suppressing MTHFD1L-formate axis.

Autor: Cui L; School of Dentistry, University of California, Los Angeles, California, USA.; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA., Zhao X; Stomatological Hospital, Southern Medical University, Guangzhou, China., Jin Z; School of Dentistry, University of California, Los Angeles, California, USA.; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA., Wang H; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China., Yang SF; Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.; Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan., Hu S; School of Dentistry, University of California, Los Angeles, California, USA.; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA.
Jazyk: angličtina
Zdroj: Journal of pineal research [J Pineal Res] 2021 Dec; Vol. 71 (4), pp. e12767. Date of Electronic Publication: 2021 Oct 02.
DOI: 10.1111/jpi.12767
Abstrakt: Metabolic remodeling is now widely recognized as a hallmark of cancer, yet its role in head and neck squamous cell carcinoma (HNSCC) remains largely unknown. In this study, metabolomic analysis of melatonin-treated HNSCC cell lines revealed that exogenous melatonin inhibited many important metabolic pathways including folate cycle in HNSCC cells. Methylenetetrahydrofolate dehydrogenase 1 like (MTHFD1L), a metabolic enzyme of the folate cycle regulating the production of formate, was identified as a downstream target of melatonin. MTHFD1L was found to be markedly upregulated in HNSCC, and MTHFD1L overexpression was significantly associated with unfavorable clinical outcome of HNSCC patients. In addition, MTHFD1L promoted HNSCC progression in vitro and in vivo and reversed the oncostatic effects of exogenous melatonin. More importantly, the malignant phenotypes suppressed by knockdown of MTHFD1L or exogenous melatonin could be partially rescued by formate. Furthermore, we found that melatonin inhibited the expression of MTHFD1L in HNSCC cells through the downregulation of cyclic AMP-responsive element-binding protein 1 (CREB1) phosphorylation. Lastly, this novel regulatory axis of melatonin-p-CREB1-MTHFD1L-formate was also verified in HNSCC tissues. Collectively, our findings have demonstrated that MTHFD1L-formate axis promotes HNSCC progression and melatonin inhibits HNSCC progression through CREB1-mediated downregulation of MTHFD1L and formate. These findings have revealed new metabolic mechanisms in HNSCC and may provide novel insights on the therapeutic intervention of HNSCC.
(© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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